It has long been appreciated that the continuous release of certain drugs over an extended period following a single administration could have significant practical advantages in clinical practice, and compositions have already been developed to provide extended release of a number of clinically useful drugs, after oral dosing (see, for example Remington's Pharmaceutical Sciences, published by Mack Publishing Company, Easton, Pennsylvania, USA, 15th Edition, 1975, pages 1618-1631), after parenteral administration (ibidem, pages 1631-1643),and after topical administration (see, for example, United Kingdom Patent Number 1,351,409). A suitable method of parenteral administration is the sub-dermal injection or implantation of a solid body, for example a pellet or a film, containing the drug, and a variety of such implantable devices has been described. In particular, it is known that, for many drugs, suitable implantable devices or injectable microparticle suspensions for providing extended drug release may be obtained by encapsulating the drug in a biodegradable polymer, or by dispersing the drug in a matrix of such a polymer, so that the drug is released as the degradation of the polymer matrix proceeds.
Suitable biodegradable polymers for use in sustained release formulations are well known, and include polyesters, which gradually become degraded by hydrolysis when placed in an aqueous, physiological-type environment. Particular polyesters which have been used are those derived from hydroxycarboxylic acids, and much prior art has been directed to polymers derived from alpha hydroxycarboxylic acids, especially lactic acid in both its racemic and optically active forms, and glycolic acid, and copolymers thereof-see, for example, U.S. Pat. Nos. 3,773,919 and 3,887,699; Jackanicz et al., Contraception, 1973, 8, 227-234; Anderson et al., ibidem, 1976, 11, 375-384; Wise et al., Life Sciences, 1976, 19, 867-874; Woodland et al., Journal of Medicinal Chemistry, 1973, 16, 897-901; Yolles et al., Bulletin of the Parenteral Drug Association, 1976, 30, 306-312; Wise et al., Journal of Pharmacy and Pharmacology, 1978, 30, 686-689 and 1979, 31, 201-204.
It is to be appreciated that "sustained" or "extended" release of a drug may be either continuous or discontinuous. For example, the release of a polypeptide from a polylactide polymer as described in UK Patent Specification No. 1,325,209 is often preceded by a significant induction period, during which no polypeptide is released, or is biphasic, and comprises an initial period during which some polypeptide is released, a second period during which little or no polypeptide is released, and a third period during which most of the remainder of the polypeptide is released. By contrast, it is an object of the present invention to provide compositions of polypeptides from which, apart possibly from a relatively short initial induction period, the polypeptide is released continuously, with no periods during which little or no polypeptide is released. The words "continuous release" are used in this specification solely to describe a release profile which is essentially monophasic, although it may have a point of inflection, but certainly has no "plateau" phase when cumulative release of drug is plotted as a function of time.
In our European Patent No. 58,481 we describe continuous release pharmaceutical compositions which enable essentially monophasic release of acid stable polypeptides to be obtained. These compositions, in general, comprise a polylactide, which is a polymer of lactic acid alone, a copolymer of lactic and glycolic acids, a mixture of such polymers, a mixture of such copolymers or a mixture of such polymers and copolymers, and an acid-stable (as hereinafter defined) polypeptide, which is not significantly hydrolysed under the conditions encountered within the composition during the period of use envisaged, which composition, when placed in an aqueous physiological-type environment (as hereinafter defined), releases the polypeptide into the aqueous physiological-type environment in continuous manner, giving a release profile which is essentially monophasic, although it may have a point of inflection, but certainly has no "plateau" phase, over a period of at least one week.
As stated above European Patent Publication No 58,481 relates to formulations of polypeptides which are stable under the conditions encountered within the claimed formulation. Certain polypeptides, however, such as native [Met.sup.-1 ] human G-CSF are inherently unstable under such conditions, suffering from a range of instability problems including inter alia the tendency to aggregate. The present invention is based on the discovery that conjugation with a water soluble polymer may overcome or at least ameliorate problems of instability present in certain polypeptides that would not otherwise be stable under the conditions encountered within the depot and would therefore not release adequately. The present invention is also based on the discovery that the use of a physiologically active substance in which a physiologically active polypeptide is covalently conjugated to a water soluble polymer, improves release profile over the corresponding unconjugated polypeptide in continuous release pharmaceutical compositions.
Recently Hora M. S. et.al have published in Proceed. Intern Symp. Control. Rel. Bioact. Mater. 16, (1989) No 268 on pages 509-510 the development of a controlled release microsphere formulation of interleukin-2. Hora M. S. et al demonstrate that a triphasic release pattern is obtained when pegylated interleukin-2 (IL-)2 covalently conjugated with polyethylene glycol (PEG) and referred to hereinafter as PEG IL-2) in the presence of foetal calf serum is released from poly (DL-lactide-co-glycolide) microspheres and further that a 5- to 15- day long lag or induction period is encountered. Hora M. S. et al seek to overcome the identified problems by attempting to improve the wetting and resolubilisation of the PEG IL-2 by the use of human serum albumin (HSA). This attempt introduces a further problem, that is the presence of solubilising protein. The presence of such protein in a pharmaceutical formulation is disadvantageous, inter alia because it enhances the risk of adverse side reaction and impedes analytical accuracy.
Furthermore the Hora M. S. et al publication referred to above fails to define either the solubility characteristics of the poly (Dl-lactide-co-glycolide)polymer (specifically whether the polymer is soluble or insoluble in benzene) or the polydispersity (as hereinafter defined). In the absence of these facts and in the absence of the method of preparation the work could not be repeated and the publication is thus not enabling. It is further noted that the publication additionally fails to define the molecular weight of the polyethylene glycol (PEG) or the level of pegylation, both of which factors are necessary if the published work is to be repeated.
In view of the poor continuous release results obtained by Hora M. S. et al with pegylated IL-2 it is particularly surprising that in accordance with the present invention such a good release profile should be obtainable by the use of physiologically active polypeptides covalently conjugated to a water soluble polymer.